In the past decade, we have enjoyed thrilling advancement in revealing the essential roles played by the SCF E3 ubiquitin ligases in regulating cell growth, signal transduction and tumor suppressor activity. SCF functions as a """"""""molecular death trigger"""""""" by tagging its target proteins with a chain of death-tag, known as ubiquitin, thereby leading to their destruction. Defective regulation of the SCF pathway is manifest in human diseases including cancers. However, we have only begun to appreciate its complex regulatory networks and we are still in our infancy with respect to developing effective pharmacologic agents. Our long-range goal is to understand the precise functioning of SCF and related """"""""molecular death triggers,"""""""" and initiate efforts to develop therapeutic strategies against human cancers. The short-term goal of our project is to determine how SCF attaches the ubiquitin death-tag to a protein target. Specifically, we found that SCF requires several players that include a work-horse enzyme named Cdc34, an activator called NeddS, and new player called DCN-1. SCF acts as a master plan-maker that coordinates the transfer of the ubiquitin death-tag to a target. Interestingly, we discovered that SCF is kept in an inactive state unless being held together with NeddS, which requires DCN-1. In addition, SCF is required to contact Cdc34, thus making the """"""""work-horse"""""""" work. Our project is to develop molecular and cellular tools to probe for various parts on SCF, NeddS, Cdc34 and DCN-1, and to determine how these parts are put together to function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061051-08
Application #
7791289
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Jones, Warren
Project Start
2002-01-15
Project End
2011-07-31
Budget Start
2010-04-01
Budget End
2011-07-31
Support Year
8
Fiscal Year
2010
Total Cost
$256,406
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Chong, Robert A; Wu, Kenneth; Kovacev, Jordan et al. (2015) Generation of a proteolytic signal: E3/E2-mediated polyubiquitination of I?B?. Methods Mol Biol 1280:339-54
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Sarikas, Antonio; Hartmann, Thomas; Pan, Zhen-Qiang (2011) The cullin protein family. Genome Biol 12:220
Wu, Kenneth; Yan, Hua; Fang, Lei et al. (2011) Mono-ubiquitination drives nuclear export of the human DCN1-like protein hDCNL1. J Biol Chem 286:34060-70

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